Although most fevers develop in response to pathology in the periphery, the characteristic rise in the level of regulated body temperature occurs only through actions of CNS temperature controls in response to pyrogens. The objective of the proposed research is to reach a better understanding of the events and biochemical changes that underlie the central mediation of fever and the normal control of body temperature. One aim arising from our previous basic and clinical research is to determine whether alterations in the circadian temperature cycle can be used as an early sign of hypothalamic injury. This idea will be tested by recording temperature cycles of unrestrained squirrel monkeys in which hypothalamic lesions are produced gradually, and by observing cycles in patients with hypothalamic injury. Our recent research suggests that a number of central peptides may have roles in normal thermoregulation and fever. We will test this possibility in rabbits by recording the effects on rectal temperature of central injections of peptides in progressive screens of these influences on normal body temperature, fever, hyperthermia and hypothermia. The content of peptides in CNS of febrile rabbits will also be measured. The idea that certain transport processes are essential for central inactivation of endogenous pyrogen was a major finding in our previous research on this project. We will investigate this relation further to learn whether the essential transport processes can occur within the parenchyma in brain regions which contain pyrogen-sensitive neurons. The puzzling failure of neonates to develop fever in the face of obvious infection will be studied by correlating fever capacity and changes in CNS amino acids that we have previously found to inhibit fever, in neonatal rabbits. The high concentrations of certain amino acids, such as taurine, during the first days after birth, followed by their marked decrease around the time that fever capacity develops, may explain the clinical fever phenomena. Data on patients with neurological disease who have dysthermia or abnormal febrile responses will also be collected in order to learn more about mediation of thermoregulation and fever in man and in order to formulate significant questions for future research.